Spironolactone inhibits the growth of cancer stem cells by impairing DNA damage response

Abstract

The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and resistance to chemotherapy, raising the need for discovering drugs that target CSCs. Previously we have found that the antihypertensive drug spironolactone impairs DNA damage response in cancer cells. Here we show that spironolactone, apart from inhibiting cancerous cell growth, is also highly toxic to CSCs. Notably, we demonstrate that CSCs have high basal levels of DNA double-strand breaks (DSBs). Mechanistically, we reveal that spironolactone does not damage the DNA but impairs DSB repair and induces apoptosis in cancer cells and CSCs while sparing healthy cells. In vivo, spironolactone treatment reduced the size and CSC content of tumors. Overall, we suggest spironolactone as an anticancer reagent, toxic to both cancer cells and, particularly to, CSCs.

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Acknowledgements

We thank the members of our laboratory for supportive discussions and lab assistance: Paola Scaffidi and Thomas Mortimer for helping with the CSCL cell system; Christel Herold-Mende for providing us SLGCs; Yuval Dor and Elad Horwitz for comet assay assistance; Dan Sarni for software advice; Batsheva Kerem for providing healthy cells; Adva Biran and Uri Ben-David for CSC advice; Nissim Benvenisty for helpful advice and Evi Soutoglou for providing anti-XPB antibodies.

Funding

This work was supported by grant 1353/12 from the Israel Science Foundation and grant 20171152 from the Israel Cancer Association, with the generous assistance of Nancy and Peter Brown through the ICA USA to MG, and by grant 1140/17 from the Israel Science Foundation and CA180 from the DKFZ-MOST Collaboration to EM.

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Correspondence to Eran Meshorer or Michal Goldberg.

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Gold, A., Eini, L., Nissim-Rafinia, M. et al. Spironolactone inhibits the growth of cancer stem cells by impairing DNA damage response. Oncogene 38, 3103–3118 (2019). https://doi.org/10.1038/s41388-018-0654-9

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